Grignard additions to 2-uloses: Synthesis of stereochemically pure tertiary alcohols

Article abstract of DOI:10.1016/j.tetlet.2004.02.106

The addition of Grignard reagents to a number of 2-uloses has been investigated. Despite initial low diastereoselectivities it was found that tuning the ketone starting materials and studying solvent effects allowed formation of a single alcohol product.

Full text of DOI:10.1016/j.tetlet.2004.02.106

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3077–3080
Grignard additions to 2-uloses: synthesis of stereochemically pure
tertiary alcohols
Ed Cleator, Catherine F. McCusker, Frank Steltzer and Steven V. Ley*
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK
Received 31 December 2003; revised 11 February 2004; accepted 19 February 2004
Abstract—The addition of Grignard reagents to a number of 2-uloses has been investigated. Despite initial low diastereoselectivities
it was found that tuning the ketone starting materials and studying solvent effects allowed formation of a single alcohol product.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Modified carbohydrate monomers are of both synthetic
and pharmaceutical interest. However, the synthesis of
chiral tertiary alcohols derived fromuloses has received
little attention.1;2 There are only a few examples of
Grignard additions to C-2 ketones in the literature3 and
the diastereoselectivities observed vary considerably.
This lack of precedent testifies to the difficulty in per-
forming diastereoselective additions of this type to C-2
uloses. During the course of a natural product synthesis
we required chiral alcohol 1 and therefore examined its
preparation froma carbohydrate source (Scheme 1).
graphy.4 Following literature procedures the desired C-3
OPMB protected alcohol 3 could be generated on a
large scale in a 36% yield. Subsequent Swern oxidation
of 3 gave the desired C-2 ulose 4 in excellent yield
(Scheme 2).5 Ulose 4 was then treated with allylmag-
nesiumbromide in THF at À78 ꢁC to give a 1:2 mixture
of diastereomers 5a and 5b in a 78% yield. The diaste-
reoselectivity obtained in this reaction has been previ-
ously described by Yoshimura et al.6 Selective reduction
of the benzylidene acetal7 on treatment with TFA/tri-
ethylsilane in CH2Cl2 gave a separable mixture of triols
1
6a and 6b. Nuclear Overhauser effect analysis in the H
NMR spectra showed the major product to be the
undesired C-2 isomer 6a.
As the C-4 OH was to be removed later in the synthesis,
a number of carbohydrate starting materials were con-
sidered. The initial starting point was commercially
available (þ)-(4,6-benzylidene)methyl-a-
D
-glucopyran-
Although our initial results were therefore disappoint-
ing, previous work by Gurjar and Hotha suggested that
similar diastereoselective additions were susceptible to
solvent effects.8 Pleasingly, this was found to be case for
4 and by simply changing the solvent from THF to
toluene–CH2Cl2 (2:1)9 the reaction proceeded with a 2:1
preference for the desired alcohol 5b. Varying the sol-
vent further did not lead to any significant enhancement
in diastereoselectivity (Table 1).
oside 2. Mono-para-methoxybenzyl (PMB) protection
of 2 is possible using tin acetal chemistry albeit with
poor selectivity and only moderate yield however, the
two regioisomers are separable by column chromato-
OP
OP
O
OH
OP'
OP'
O
OP'
OP'
Fromthe results shown in Table 1 it became apparent
that 5b was formed preferentially in solvents, which are
unable to chelate to the Grignard reagent. This sug-
gested that the observed diastereoselectivity may be due
to intramolecular chelation of the Grignard reagent.
Similar diastereoselective additions on chiral, protected
a-hydroxyketones have been achieved by the addition of
MgBr2ÆEt2O prior to organometallic addition.10 It is
thought that a similar chelation mechanism is respon-
sible in this addition and that excess Grignard reagent is,
RO
O
RO
1
Scheme 1. Retrosynthesis of tertiary alcohol 1: P and P0 are ortho-
gonal protecting groups.
Keywords: Carbohydrates; Tertiary alcohols; Grignard reagents.
* Corresponding author. Tel.: +44-1223-336398; fax: +44-1223-
336442; e-mail: svl1000@cam.ac.uk
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.02.106

3078
E. Cleator et al. / Tetrahedron Letters 45 (2004) 3077–3080
OH
OPMB
OPMB
HO
O
Ph
HO
O
Ph
O
O
Ph
a
b
O
O
O
MeO
O
MeO
O
MeO
O
2
3
4
c
OPMB
OH
OH
OH
O
Ph
OH
OH
d
O
O
OBn
OBn
MeO
O
MeO
MeO
O
5b
6a
OH
OPMB
OH
OH
O
Ph
O
MeO
O
6b
5a
Scheme 2. Reagents and conditions: (a) Bu2SnO, toluene, reflux, 5 h, then PMB-Cl, TBABr, reflux, 24 h, 36%; (b) (COCl)2, DMSO, Et3N, CH2Cl2,
À78 ꢁC, rt, 100%; (c) allylmagnesium bromide (1 M in Et2O), THF, À78 ꢁC, 1 h, 78% (2:1, 5a:5b); (d) Et3SiH (5 equiv), TFA (5 equiv), CH2Cl2,
0 ꢁC fi rt, 93%, (1:2, 6a:6b).
Table 1. Solvent effects on product distribution for the addition of
allylmagnesium bromide to ulose 4
With these initially promising results in hand our
attention was then turned to improving the selectivity of
Entry Conditions
Ratio 5b:5a Yield (%)
the mono-PMB protection. An obvious solution was to
switch fromglucopyranoside to mannose as the starting
carbohydrate. Using standard tin acetal chemistry, PMB
protection is possible in excellent yield solely at the C-3
OH.11 Removal of the C-4 OH prior to the Grignard
reaction was also possible. Treatment of commercially
1
2
3
4
5
6
Toluene, À78 ꢁC
2:1
2:1
76
82
79
80
74
68
Toluene–CH2Cl2 (2:1), À78 ꢁC
Toluene–CH2Cl2 (3:1), À78 ꢁC
Toluene–CH2Cl2 (4:1), À78 ꢁC
CH2Cl2, À78 ꢁC
2:1
2:1
1.5:1
1.2:1
DME, À78 ꢁC
available a-benzyl-D-mannose 7 in the presence of
imidazole with TBDPSCl in DMF gave the C-6 pro-
tected triol. The crude triol was subsequently treated
with 2,2-dimethoxypropane in acetone in the presence of
a catalytic amount of CSA to give the C-4 alcohol 8 in a
98% yield. Alcohol 8 was then converted into xanthate 9
in quantitative yield upon treatment with NaHMDS in a
THF/CS2 solution at À78 ꢁC followed by addition of
iodomethane and warming to room temperature.12
When subjected to standard Barton McCombie13 con-
ditions of Bu3SnH/AIBN in refluxing toluene 9 was
smoothly converted into the corresponding 4-deoxy-
mannose derivative 10. Selective removal of the iso-
propylidene acetal was accomplished by heating 10 in a
4:1 AcOH/H2O solution at 80 ꢁC for 2 h. Selective
C-3 OH PMB protection followed by Swern oxidation
gave the desired 4-deoxyulose 11. Treatment of ulose 11
with our optimised Grignard conditions gave a 3:1
mixture of alcohols in favour of desired alcohol 12a
(Scheme 4). This marginal lowering of diastereoselec-
tivity is ascribed to the absence of the second ring
making 11 more flexible (cf. ulose 4).
by coordination to the C-3 OH and ketone oxygen,
blocking the top face of the ketone in an unreactive
conformation. This then allows attack from the lower
face by another equivalent of the Grignard reagent
leading to the observed diastereoselectivity (Scheme 3).
This hypothesis was further supported by the fact that,
when we removed the chelating solvent which the
Grignard reagent was supplied in (Et2O) and solubilised
the residue with toluene–CH2Cl2; the highest levels of
diastereoselectivity were observed. Using the conditions
described in Scheme 3 led to an optimal 4.5:1 ratio of
products in favour of desired alcohol 5b, which was
easily separable from 5a by chromatography on silica
gel.
OPMB
OH
O
Ph
Br
O
Mg
O
O
a
O
MeO
O
O
O
Ph
O
5b
5a : 5b, 1 : 4.5
Ar
OPMB
OH
With the second ring required to enhance the diastereo-
selectivity, a modified approach to alcohol 1 starting
O
Ph
O
from b-D-galactose was devised. It was reasoned that as
the C-4 OH is b in galactose a suitable protection
strategy might allow better diastereoselectivity. Synthe-
MgBr
MeO
O
5a
sis of b-O-pentenylgalactose 13 from b-D-galactose
pentaacetate has been previously reported in the litera-
Scheme 3. Reagents and conditions: (a) allylmagnesium bromide, 3:1
toluene–CH2Cl2, À78 ꢁC, 84%.

E. Cleator et al. / Tetrahedron Letters 45 (2004) 3077–3080
3079
OH
S
SMe
O
O
HO
OH
a,b
O
O
OH
O
c
OH
BnO
O
OTBDPS
OTBDPS
BnO
BnO
O
O
7
8
9
d
OPMB
O
OH
OTBDPS
OPMB
O
BnO
H
H
O
O
e,f,g
H
12a
H
h
OTBDPS
OTBDPS
BnO
O
BnO
O
OPMB
OH
11
10
OTBDPS
BnO
O
12b
12a : 12b : 3 : 1
Scheme 4. Reagents and conditions: (a) TBDPSCl, DMF, imidazole, rt; (b) 2,2-dimethoxypropane, acetone, CSA (cat), 98% over two steps; (c) THF,
CS2 then NaHMDS (1 M in THF), 20 min, À78 ꢁC; then MeI, À78 ꢁC fi rt, 100%; (d) Bu3SnH, AIBN, toluene, 90 ꢁC, 84%; (e) AcOH–H2O (4:1),
80 ꢁC, 2 h, 78%; (f) Bu2SnO, MeOH, reflux, 2 h, then DMF, PMB-Cl, CsF, NaI, rt, 24 h, 93%; (g) (COCl)2, DMSO, Et3N, CH2Cl2, À78 ꢁC, rt, 100%;
(h) allylmagnesium bromide, 3:1 toluene–CH2Cl2, À78 ꢁC, 1 h, 78% (3:1, 12a: 12b).
O
OH
O
OTBDPS
PenO
O
OH
O
15a
HO
OH
a,b
O
c,d
HO
OH
O
PenO
O
OTBDPS
OH
PenO
O
O
14
13
OTBDPS
PenO
O
15b
15a : 15b : 8 : 1
Scheme 5. Reagents and conditions: (a) TBDPSCl, DMF, imidazole, rt; (b) 2,2-dimethoxypropane, acetone, CSA (cat), 85% over two steps;
(c) (COCl)2, DMSO, Et3N, CH2Cl2, À78 ꢁC fi rt; (d) allylmagnesium bromide, THF, À78 ꢁC, 1 h, 76% over two steps (8:1, 15a:15b).
ture.14 The O-pentenyl group was chosen for its ease of
Ph
OMe
Nu
removal at a latter stage in the synthesis. Although it is
worth noting that switching fromthe a-sugar to the
b-sugar (cf. 4 or 11 vs 13) may also have a consequence
on the facial selectivity of this addition. In 13 the cis C-1
and C-3 substituents occupy equatorial positions, this
may lead to the major nucleophilic approach from the
opposite lower face. Conversely in 4 and 11 C-1 and C-3
have a trans relationship with the C-1 group occupying
an axial position and hence, as is observed, directing the
Nu (minor)
OTBDPS
O
O
O
O
O
O
O
O
POMO
O
POMO
Nu (major)
Nu
Figure 1. Proposed inhibition of nucleophile approach fromthe upper
face.
15
nucleophilic attack preferentially fromthe top face.
This increased diastereoselectivity was thought to be
primarily due to the isopropylidene acetal blocking the
upper face of 14. Although the presence of the b-sub-
stituents at C-1 and C-3 may also influence this
enhanced selectivity (as previously discussed). There-
fore, we reasoned that if the protecting group ring was
formed between the C-4 and C-6 OH groups the reac-
tion of the nucleophile fromthe top face might be
inhibited altogether (Fig. 1).
When 13 was treated with TBDPSCl followed by 2,2-
dimethoxypropane as described for the mannose deriv-
ative, the C-2 OH alcohol 14 was formed in 85% yield.
Swern oxidation of 14 gave the corresponding ulose,
which was directly treated at À78 ꢁC with allylmagne-
sium bromide giving rise to an improved 8:1 mixture of
alcohols 15a and 16b in favour of the desired alcohol
15a (Scheme 5).

3080
E. Cleator et al. / Tetrahedron Letters 45 (2004) 3077–3080
OPMB
OH
O
OPMB
OH
O
Ph
HO
OH
HO
O
Ph
a,b
c,d
O
OH
O
PenO
O
PenO
PenO
O
13
16
17
Scheme 6. Reagents and conditions: (a) benzaldehyde dimethylacetal, MeCN, CSA (cat), reflux, 1 h, 88%; (b) Bu2SnO, toluene, reflux, 2 h, then
PMB-Cl, TBAI, reflux, 24 h, 79%; (c) (COCl)2, DMSO, Et3N, CH2Cl2, À78 ꢁC fi rt; (d) allylmagnesium bromide, THF, À78 ꢁC, 1 h, 76% over two
steps.
Table 2. Addition of Grignard reagents to ulose 16
Acknowledgements
Entry
Conditions
Yield (%)
We gratefully acknowledge the financial support from
the EPSRC, the BP endowment and a Novartis
Research Fellowship (to S.V.L.).
1
2
3
MeMgBr (3 equiv), THF, À78 ꢁC
EtMgBr (3 equiv), THF, À78 ꢁC
PhMgBr (3 equiv), THF, À78 ꢁC
88
70
67
References and notes
1. Addition to C-3 uloses; (a) Box, L. L.; Roberts, V. G. S.;
Earle, V. E. Carbohydr. Res. 1981, 96, 215; (b) Dyong, I.;
Schulte, G. Chem. Ber. 1981, 114, 1484; (c) Horito, S.;
Asano, K.; Umemura, K.; Hironobu, H.; Yoshimura, J.
Carbohydr. Res. 1983, 121, 175; (d) Yoshimura, J.; Hong,
N.; Sato, K. Chem. Lett. 1980, 1131; (e) Lipshutz, B. H.;
Elworthy, S. L.; Todd, R. Tetrahedron 1988, 11, 3355; (f)
Pietsch, M.; Walter, M.; Buchholz, K. Carbohydr. Res.
1994, 254, 183.
2. Addition to C-4 uloses; (a) Sato, K.; Kubo, K.; Hong, N.;
Kodama, H.; Joshima, J. Bull. Chem. Soc. Jpn. 1982, 3,
938; (b) Chiu, A. K. B.; Hough, L.; Richardson, A. C.;
Toufeili, I. A.; Dziedzic, S. Z. Carbohydr. Res. 1987, 162,
316.
Accordingly, derivative 13 was treated with benzalde-
hyde dimethyl acetal in MeCN at reflux in the presence
of a catalytic amount of CSA to give the 4,6-benzylidene
acetal. Mono-PMB protection of 4,6-benzylidene acetal,
using tin chemistry, was much more selective than with
pyranoside 2 and galactose 13 and occurred in quanti-
tative yield with a 4:1 ratio in favour of the desired C-3
PMB protected alcohol 16.16 Swern oxidation of 16 gave
the unstable ulose, which was directly treated with
allylmagnesium bromide in THF at À78 ꢁC. Analysis of
the crude reaction mixture showed that alcohol 17 had
been formed as a single diastereomer, and could be
isolated after chromatography in 76% yield for the
two steps. The assigned structure was confirmed by
X-ray diffraction analysis of a single crystal of 17
(Scheme 6).
3. Schmeichel, M.; Redlich, H. Synthesis 1996, 1002.
4. Jenkins, D. J.; Potter, B. V. L. Carbohydr. Res. 1994, 265,
145.
€
5. Rekaie, E.; Rubinstenn, G.; Mallet, J. M.; Sinay, P.
Synlett 1998, 831.
6. Yoshimura, J.; Kawauchi, N.; Yasumori, T.; Sato, K.;
Hashimoto, H. Carbohydr. Res. 1984, 133, 255.
7. Manning, D. D.; Bertozzi, C. R.; Rosenand, S. D.;
Kiessling, L. L. Tetrahedron Lett. 1996, 37, 1953.
8. Gurjar, M. K.; Hotha, S. Heterocycles 2000, 53, 1885.
9. (a) Turner, R. M.; Lindell, S. D.; Ley, S. V. J. Org. Chem.
1991, 56, 5739; (b) Turner, R. M.; Lindell, S. D.; Ley, S. V.
Synlett 1993, 748.
To test the generality of the Grignard addition, three
common Grignard reagents were added to the ketone
derived fromsubstrate
16 after Swern oxidation.
All products were generated as single diastereomers
and in good yields (Table 2). It is worth noting that
as the size of Grignard reagent increases the yield
of product drops. The decrease in yield, albeit
small, may be due to the slower reactivity of bulky
Grignards as compared to the very reactive allyl
Grignard reagent.
10. Nicolaou, K. C.; Hwang, C.; Duggan, M. E. J. Am. Chem.
Soc. 1989, 111, 6682.
11. Cappa, A.; Marcantoni, E.; Torregiani, E.; Bartoli, G.;
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E. M.; Salvino, J. J. Am. Chem. Soc. 1993, 115, 12550.
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14. Udodong, U. E.; Rao, C. S.; Fraser-Reid, B. Tetrahedron
1992, 48, 4713.
In summary, we have shown that 2-uloses derived from
a number of modified carbohydrates undergo stereo-
selective reactions with allylmagnesium bromide. By
appropriate choice of carbohydrate starting material
and a suitable protection strategy enantiopure C-2 ter-
tiary alcohols can be prepared in excellent yields froma
variety of Grignard reagents.
15. As suggested by a referee.
16. Rekaie, E.; Rubinstenn, G.; Mallet, J. M.; Sinay, P.
Synlett 1998, 831.
€